Delta 6,7-taxols antineoplastic use and pharmaceutical compositions containing them

Abstract: This invention provides 7-deoxy-Δ 6,7 -taxol and 7-deoxy-Δ 6,7 -taxol analogs of Formula I: The compounds of Formula I are useful for the same cancers for which taxol has been shown active, including human ovarian cancer, breast cancer, and malignant melanoma as well as lung cancer, gastric cancer, colon cancer, head and neck cancer, and leukemia.

Description: Field of the Invention This invention relates to a process for the preparation of 10-desacetyltaxol, taxotere and analogues thereof. Background of the Invention Taxol and taxotere are potent anticancer agents. US-A-5248796 relates to 10-desacetoxy-11,12-dihydrotaxol-10,12(18)-diene derivatives and the preparation of 10-desacetoxytaxol. Samaranayake et al., J. Org. Chem ., 1991, 56 , 5114, discloses a method for removal of the acyl group from the 10-position of taxol and baccatin structures, using zinc bromide in methanol. This method gives a number of other products in addition to the desired deacylation product. Summary of the Invention The present invention is a deacetylation process, using hydrazine, that is defined in the claims. Description of the Invention In an embodiment of the invention, the reaction of taxol and taxol analogs I wherein R 15 is acetyl, baccatin III or baccatin III analogs 2, wherein R 6 is acetyl, with hydrazine comprises a particularly advantageous method for preparation of 10-deacetyltaxol, 10-deacyltaxol analogs (1, R 15 = H), 10-deacetylbaccatin III, and 10-deacylbaccatin III analogs (2, R 6 = H). The reaction with hydrazine gives almost exclusively the desired deacylation product. The reaction may be performed at room temperature in an organic solvent and usually requires as little time as 15 min or as much as 24 hr, depending on the substrate. The preferred solvent for the reaction is 95% ethanol and 98% hydrazine is the preferred form of the reagent. The following Examples illustrate the invention. Example 1 Taxotere 25 mg (0.029 mM) 10-acetyltaxotere is stirred at room temperature under nitrogen in 1.0 mL 95% ethanol. 2 drops anhydrous hydrazine are added and left to react for 1.5 hours, when TLC showed the reaction to be mostly complete. The reaction is partitioned between water-methylene chloride. The aqueous layer is back-extracted with methylene chloride. The organic layers are combined, dried over sodium sulfate and evaporated under vacuum. The crude product is chromatographed over 3 g silica gel, eluting with 70-30 ethyl acetate-hexane. Fractions of 1 mL are collected, and analysed by TLC. Fractions 14-28 contain the product and are combined and evaporated under vacuum. TLC: silica gel 60; 70-30 EtOAc-hexane; Rf: 0.33. 1 H NMR (CDCl 3 , TMS) δ 1.12 (s, 3H); 1.23 (s, 3H); 1.34 (s, 9H); 1.74 (s, 3H); 1.85 (s, 3H); 2.37 (s, 3H); 2.56 (m, 1H); 3.53 (bs, 1H); 3.90 (d, 1H); 4.18 (d, 1H); 4.21 (m, 1H); 4.30 (d, 1H); 4.32 (s, 1H); 4.62 (bs, 1H); 4.94 (d, 1H); 5.23 (s, 1H); 5.28 (bs, 1H); 5.52 (d, 1H); 5.66 (d, 1H); 6.20 (t, 1H); 7.25-7.45 (m, 6H); 7.50 (t, 2H); 7.61 (t, 1H); 8.11 (d, 2H). Example 2 10-Deacetyltaxol A solution of taxol (0.026 g, 0.030 mmol) and 98% hydrazine (0.035 g, 1.1 mmol) in 95% ethanol (1.0 mL) is stirred at room temperature for 2 hours. The solution is poured into water and ether, the mixture is shaken well, and the layers are separated. The aqueous layer is extracted with additional ether. The combined ether extracts are dried over Na 2 SO 4 , filtered and concentrated, giving 0.021 g ofthe title compound; its 1 H NMR spectrum in CDCl 3 is identical to the spectrum reported for 10-deacetyltaxol (Ringel, I.; Horwitz, S. B. J. Pharmacol. Exp. Ther ., 1987, 242 , 692) and is identical to the spectrum of an authentic sample. Example 3 10-Deacetylbaccatin III A solution of baccatin m (0.024 g, 0.041 mmol) in 95% ethanol (1.0 mL) is prepared by warming the mixture. The solution is cooled to room temperature, 98% hydrazine (0.035 g, 1.1 mmol) is added and the solution is stirred at room temperature for 24 hours. The solution is poured into water/ether, shaken well, and the layers are separated. The ether layer is washed with water, dried (Na 2 SO 4 ), filtered, and concentrated, giving 0.010 g of the title compound; its 1 H NMR spectrum in CDCl 3 (sparingly soluble) is identical to that of an authentic sample of 10-deacetylbaccatin III.

Claims: A process of preparing a comppund of formula: wherein R 1 is selected from the group consisting of -CH 3 , -C 6 H 5 or phenyl substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 3 alkoxy, halo, C 1 -C 3 alkylthio, trifluoromethyl, C 2 -C 6 dialkylamino, hydroxy or nitro, -2-furyl, 2-thienyl, 1-naphthyl, 2-naphthyl or 3,4-methylenedioxyphenyl; R 2 is selected from the group consisting of -H, -NHC(O)H,-NHC(O)C 1 -C 10 alkyl, -NHC(O)phenyl, -NHC(O)phenyl substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 3 alkoxy, halo, C 1 -C 3 alkylthio, trifluoromethyl, C 2 -C 6 dialkylamino, hydroxy or nitro, -NHC(O)C(CH 3 )=CHCH 3 , -NHC(O)OC(CH 3 ) 3 , -NHC(O)OCH 2 phenyl, -NH 2 , -NHSO 2 -4-methylphenyl, -NHC(O)(CH 2 ) 3 COOH, -NHC(O)-4-(SO 3 H)phenyl, -OH, -NHC(O)-1-adamantyl, -NHC(O)O-3-tetrahydrofuranyl, -NHC(O)O-4-tetrahydropyranyl, -NHC(O)CH 2 C(CH 3 ) 3 , -NHC(O)C(CH 3 ) 3 , -NHC(O)OC 1 -C 10 alkyl, -NHC(O)NHC 1 -C 10 alkyl, -NHC(O)NHPh, -NHC(O)NHPh substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 3 alkoxy, halo, C 1 -C 3 alkylthio, trifluoromethyl, C 2 -C 6 dialkylamino, or nitro, -NHC(O)C 3 -C 8 cycloalkyl, -NHC(O)C(CH 2 CH 3 ) 2 CH 3 , -NHC(O)C(CH 3 ) 2 CH 2 Cl, -NHC(O)C(CH 3 ) 2 CH 2 CH 3 , phthalimido, -NHC(O)-1-phenyl-1-cyclopentyl, -NHC(O)-1-methyl-1-cyclohexyl, -NHC(S) NHC(CH 3 ) 3 or -NHC(O)NHC(CH 3 ) 3 ; R 3 is selected from the group consisting of -H, -NHC(O)phenyl or -NHC(O)OC(CH 3 ) 3 , with the overall proviso that one of R 2 and R 3 is -H but R 2 and R 3 are not both -H; Bz is -C(O)phenyl; and Ac is C(O)CH 3 ; which comprises reacting a compound of formula: wherein R 1 , R 2 , R 3 , Bz and Ac are as defined above; hydrazine. A process of preparing a compound of formula: wherein Bz is C(O)phenyl and Ac is C(O)CH 3 ; which comprises reacting a compound of formula: with hydrazine.

Inventors: JOHNSON ROY A, KELLY ROBERT C, NIDY ELDON G, SKULNICK HARVEY I, JOHNSON, ROY A., KELLY, ROBERT C., NIDY, ELDON G., SKULNICK, HARVEY I.
Applicants: UPJOHN CO, PHARMACIA & UPJOHN COMPANY
Application year: 1994
Main classification: C07D305
IPC codes: C07D409, C07D413, C07D305, C07D405, C07D407, A61K31, C07D263